Oxo-substituted cyclohexyl-1,4-diamine compounds

ABSTRACT

Novel cyclohexyl-1,4-diamine compounds corresponding to formula I: 
                         
methods for their production, pharmaceutical formulations containing these compounds, methods of producing such pharmaceutical formulations and related methods of treating or inhibiting certain diseases or conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International patent applicationSerial No. PCT/EP2005/004907 filed May 6, 2005 which claims benefit toGerman patent application Serial No. 10 2004 023 501.5 filed May 10,2004, the entire disclosures of which are hereby incorporated in theirentirety.

FIELD OF THE INVENTION

The present invention relates to substituted cyclohexyl-1,4-diaminecompounds, to processes for the production thereof, to pharmaceuticalformulations containing these compounds, to methods of producing suchpharmaceutical formulations and to related methods of treating orinhibiting certain diseases or conditions.

BACKGROUND OF THE INVENTION

The treatment of chronic and non-chronic pain conditions has greatimportance in medicine. There is a worldwide need for effective methodsof treating pain. The urgent need for action for patient-oriented andpurposeful treatment of chronic and non-chronic pain conditions, thisbeing taken to mean the successful and satisfactory treatment of painfor the patient, is documented in the large number of scientific paperswhich have recently appeared in the field of applied analgesics andfundamental research work on nociception.

Conventional μ-opioids such as morphine are very effective in thetreatment of strong to very strong pain and are of great importance forthe treatment of pain. However, it may be advantageous if, in additionto the μ-opioid receptor, further opioid receptors, in particular theORL1 receptor, are affected, since pure μ-opioids also have undesirableside effects, such as obstipation and respiratory depression, and mayalso lead to addiction. The opioid receptors δ, κ and ORL1 are alsoinvolved in the state of pain (Opioids: Introduction, pp. 127-150,Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry andPharmacology to Clinical Application, Wiley VCH, 2002).

It is also known that influencing of serotonin and/or noradrenalinre-uptake can be beneficial to the effects and side effects of opioids(Example: Tramadol, see Opioids with Clinical Relevance: Tramadol,228-230 in: Analgesics—From Chemistry and Pharmacology to ClinicalApplication, Wiley VCH, 2002).

The ORL1 receptor is also involved in the regulation of furtherphysiological and pathophysiological processes. These include inter alialearning and memory formation (Manabe et al, Nature, 394, 1997, pp.577-581), Hörvermögen [Hearing capacity] (Nishi et al, EMBO J., 16,1997, pp. 1858-1864) and numerous further processes. In a synopsis byCalo et al (Br.J. Pharmacol., 129, 2000, 1261-1283) there is an overviewof the indications or biological procedures, in which the ORL1 receptorplays a part or could highly probably play a part. Mentioned inter aliaare: analgesics, stimulation and regulation of nutrient absorption,effect on μ-agonists such as morphine, treatment of withdrawal symptoms,reduction of the addiction potential of opioids, anxiolysis, modulationof motor activity, memory disturbances, epilepsy; modulation ofneurotransmitter release, in particular of glutamate, serotonin anddopamine, and therefore neurodegenerative diseases; influencing thecardiovascular system, triggering an erection, diuresis,anti-natriuresis, electrolyte balance, arterial blood pressure,water-retention disorders, intestinal motility (diarrhea), relaxation ofthe respiratory tract, micturation reflex (urinary incontinence). Theuse of agonists and antagonists such as anoretics, analgesics (also whenadministered with opioids) or nootropics will also be discussed.

Structurally related compounds which have an affinity with the ORL1receptor are known from the prior art (WO 02090317). The effect onnoradrenalin and serotonin re-uptake has not previously been describedfor this structural class.

SUMMARY OF THE INVENTION

An object of the present invention was to provide pharmaceuticalcompositions which act on the opioid receptor system and are thussuitable for pharmaceutical compositions, in particular for thetreatment of the various diseases associated with this system accordingto the prior art and for use in the indications mentioned therein. Thecompounds are also intended to influence noradrenalin and serotoninre-uptake.

The invention therefore relates to substituted cyclohexyl-1,4-diaminecompounds of general formula I,

wherein

R¹ and R² independently of one another represent H; respectivelysaturated or unsaturated, branched or unbranched, singly or multiplysubstituted or unsubstituted C₁₋₅ alkyl; respectively singly or multiplysubstituted or unsubstituted C₃₋₈-cycloalkyl; or respectively singly ormultiply substituted or unsubstituted aryl, C₃₋₈ cycloalkyl orheteroaryl bound by C₁₋₃ alkyl;

or the radicals R¹ and R² together represent CH₂CH₂OCH₂CH₂,CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆,

wherein R¹⁰ represents H; respectively saturated or unsaturated,branched or unbranched, singly or multiply substituted or unsubstitutedC₁₋₅ alkyl; respectively singly or multiply substituted or unsubstitutedC₃₋₈ cycloalkyl; respectively singly or multiply substituted orunsubstituted aryl or heteroaryl; or respectively singly or multiplysubstituted or unsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl boundby C₁₋₃ alkyl; respectively substituted or unsubstituted C(O)phenyl,C(O)heteroaryl, C(O)C₁₋₅ alkyl;

R³ represents respectively saturated or unsaturated, branched orunbranched, singly or multiply substituted or unsubstituted C₁₋₅ alkyl;respectively singly or multiply substituted or unsubstituted C₃₋₈cycloalkyl; respectively unsubstituted or singly or multiply substitutedaryl or heteroaryl; respectively unsubstituted or singly or multiplysubstituted aryl, heteroaryl or C₃₋₈ cycloalkyl bound by a C₁₋₃ alkylgroup;

X represents a branched or unbranched, unsubstituted or singly ormultiply substituted alkyl chain (CH₂)_(n), aryl or C₃₋₈ cycloalkyl, orrespectively substituted or unsubstituted aryl or C₃₋₈ cycloalkyl boundby a C₁₋₃ alkyl chain, where n=0, 1, 2, 3, 4, 5,

R⁴ represents respectively saturated or unsaturated, branched orunbranched, singly or multiply substituted or unsubstituted C₁₋₅ alkyl;respectively singly or multiply substituted or unsubstituted C₃₋₈cycloalkyl; respectively singly or multiply substituted or unsubstitutedaryl or heteroaryl; or respectively singly or multiply substituted orunsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl bound by C₁₋₃ alkyl,

in the form of the racemate; the enantiomers, diastereomers, mixtures ofthe enantiomers or diastereomers or an individual enantiomer ordiastereomer; the bases and/or salts of physiologically acceptable acidsor cations.

The compounds according to the invention exhibit good binding to the μreceptor and the ORL1 receptor, but also to other opioid receptors.Surprisingly it has been found that the compounds are also goodinhibitors of noradrenalin and serotonin re-uptake. They are thereforealso suitable for treating depression and/or bulimia and/or anorexiaand/or catalepsy and/or anxiolysis and/or increasing alertness and/orlibido.

The terms “C₁₋₅ alkyl” and “C₁₋₃ alkyl” comprise, in the context of thisinvention, acyclic saturated or unsaturated hydrocarbon radicals, whichmay be branched or straight-chained and unsubstituted or singly ormultiply substituted, with 1, 2, 3, 4 or 5 C atoms or 1, 2 or 3 C atoms,i.e. C₁₋₅ alkanyls, C₂₋₅ alkenyls and C₂₋₅ alkynyls or C₁₋₃ alkanyls,C₂₋₃ alkenyls and C₂₋₃ alkynyls. Alkenyls have at least one C—C doublebond and alkynyls at least one C—C treble bond. Alkyl is advantageouslyselected from the group comprising methyl, ethyl, n-propyl, 2-propyl,n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl,neo-pentyl, ethylenyl (vinyl), ethynyl, propenyl (—CH₂CH═CH₂,—CH═CH—CH₃, —C(═CH₂)—CH₃), propinyl (—CH—C≡CH, —C≡C—CH₃),1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butynyl, pentenyl andpentynyl.

For the purposes of this invention, the term “cycloalkyl” or “C₃₋₈cycloalkyl” means cyclic hydrocarbons with 3, 4, 5, 6, 7 or 8 carbonatoms, wherein the hydrocarbons may be saturated or unsaturated (but notaromatic), unsubstituted or singly or multiply substituted. With respectto cycloalkyl, the term also comprises saturated or unsaturated (but notaromatic) cycloalkyls, in which one or two carbon atoms are replaced byan S, N or O heteroatom. C₃₋₈ cycloalkyl is advantageously selected fromthe group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl andcyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl,morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.

The term “(CH₂)₃₋₆” denotes —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂— und CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—.

The term “aryl”, according to this invention, denotes carbocyclic ringsystems comprising at least one aromatic ring, but without a heteroatomin only one of the rings, inter alia phenyls, naphthyls andphenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.The aryl radicals can also be condensed with further saturated,(partially) unsaturated or aromatic ring systems. Each aryl radical canbe present unsubstituted or singly or multiply substituted, wherein thearyl substituents may be the same or different and in any desired andpossible position of the aryl. Phenyl or naphthyl radicals areparticularly advantageous.

The term “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromaticradical, which contains at least 1 heteroatom, optionally also 2, 3, 4or 5 heteroatoms, wherein the heteroatoms may be the same or differentand the heterocycle may be unsubstituted or singly or multiplysubstituted; in the case of substitution on the heterocycle, thesubstituents may be the same or different and in any desired andpossible position of the heteroaryl. The heterocycle may also be part ofa bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygenand sulphur. It is preferred for the heteroaryl radical to be selectedfrom the group comprising pyrrolyl, indolyl, furyl (furanyl),benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl,benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl,phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl,pyrrolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, imidazolyl, triazolyl, triazinyl, quinazolinyl,carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein thebinding with the compounds of general structure I can be made via anydesired and possible ring member of the heteroaryl radical.

In conjunction with “alkyl”, the term “substituted”, according to thisinvention, denotes substitution of one or more hydrogen radicals by F,Cl, Br, I, —CN, ═O, ═S, NH₂, NH-alkyl, NH-aryl, NH-heteroaryl,NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-OH,N(alkyl)₂, N(alkyl-aryl)₂, N(alkyl-heteroaryl)₂, N(cycloalkyl)₂,N(alkyl-OH)₂, NH(C═O)alkyl, NH(C═O)aryl, NO₂, SH, S-alkyl, S-aryl,S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl,S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-aryl, O-heteroaryl, O-alkyl-aryl,O-alkyl-heteroaryl, O-cycloalkyl, O-alkyl-OH, CHO, C(═O)C₁₋₆ alkyl,C(═S)C₁₋₆ alkyl, C(═O)aryl, C(═S)aryl, C(═O)C₁₋₆ alkyl-aryl,C(═S)C₁₋₆-alkyl aryl, C(═O)-heteroaryl, C(═S)-heteroaryl,C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO₂H, CO₂-alkyl, CO₂-alkyl-aryl,C(═O)NH₂, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-cycloalkyl,C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂, C(═O)N(alkyl-heteroaryl)₂,C(═O)N(cycloalkyl)₂, SO-alkyl, SO₂-alkyl, SO₂NH₂, SO₃H, PO(O—C₁₋₆alkyl)₂, cycloalkyl, aryl or heteroaryl, wherein the term “multiplysubstituted radicals” denotes radicals that have been multiplysubstituted, for example twice or three times, either on different or onthe same atoms, for example three times on the same C atom, as in thecase of CF₃ or —CH₂CF₃, or in various positions, as in the case of—CH(OH)—CH═CH—CHCl₂. Multiple substitution can take place with the samesubstituent or with different substituents. A substituent may optionallyalso be substituted for its part; thus —O-alkyl also includes inter alia—O—CH₂—CH₂—O—CH₂—CH₂—OH.

With respect to “aryl”, “heteroaryl” and “cycloalkyl”, according to thisinvention, “singly or multiply substituted” denotes the single ormultiple, for example double, treble, quadruple or quintuple,substitution of one or more hydrogen atoms of the ring system by F, Cl,Br, I, CN, NH₂, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl,NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N(alkyl)₂,N(alkyl-aryl)₂, N(alkyl-heteroaryl)₂, N(cycloalkyl)₂, N(alkyl-OH)₂, NO₂,SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl,S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl,O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl,O-cycloalkyl, O-alkyl-OH, CHO, C(═O)C₁₋₆ alkyl, C(═S)C₁₋₆ alkyl,C(═O)aryl, C(═S)aryl, C(═O)—C₁₋₆ alkyl-aryl, C(═S)C₁₋₆ alkyl-aryl,C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl,CO₂H, CO₂-alkyl, CO₂-alkyl-aryl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NH-aryl,C(═O)NH-cycloalkyl, C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(cycloalkyl)₂, S(O)-alkyl, S(O)-aryl,SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₃H, CF₃, ═O, ═S;

alkyl, cycloalkyl, aryl and/or heteroaryl; on one atom or optionally ondifferent atoms (wherein a substituent can, in turn, optionally besubstituted). Multiple substitution takes place here using the same ordifferent substituents.

The term “salt” denotes any form of the active ingredient according tothis invention in which it assumes or is charged with an ionic form andis coupled to a counter ion (a cation or anion) or is in solution. Thisalso includes complexes of the active ingredient with other moleculesand ions, in particular complexes complexed by ionic interactions. Inparticular this denotes (and this is also a preferred embodiment of thisinvention) physiologically acceptable salts, in particularphysiologically acceptable salts with cations or bases andphysiologically acceptable salts with anions or acids or else a saltformed with a physiologically acceptable acid or physiologicallyacceptable cation.

The term “physiologically acceptable salt with anions or acids” denotes,in the context of this invention, salts of at least one of the compoundsaccording to this invention—usually protonated, for example onnitrogen—as a cation with at least one anion which are physiologicallyacceptable—in particular when applied to humans and/or mammals. In thecontext of this invention this denotes, in particular, the salt formedwith a physiologically acceptable acid, namely salts of the respectiveactive ingredient with inorganic or organic acids which arephysiologically acceptable—in particular when applied to humans and/ormammals. Examples of physiologically acceptable salts of specific acidsinclude salts of: hydrochloric acid, hydrobromic acid, sulphuric acid,methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid, saccharic acid, monomethyl sebacicacid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid,acetyl glycine, phosphoric acid, maleic acid, malonic acid, hippuricacid and/or aspartic acid. The hydrochloride salt, the citrate and thehemicitrate are particularly preferred.

The term “salt formed with a physiologically acceptable acid”, accordingto this invention, denotes salts of the respective active ingredientwith inorganic or organic acids which are physiologically acceptable—inparticular when applied to humans and/or mammals. The hydrochloride andthe citrate are particularly preferred. Examples of physiologicallyacceptable acids include: hydrochloric acid, hydrobromic acid, sulphuricacid, methane sulphonic acid, formic acid, acetic acid, oxalic acid,succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid,citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid,5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid,acetyl glycine, hippuric acid and/or aspartic acid.

The term “physiologically acceptable salt with cations or bases”denotes, in the context of this invention, salts of at least one of thecompounds according to this invention—usually a (deprotonated) acid—asan anion with at least one, preferably inorganic, cation, which arephysiologically acceptable, in particular when applied to humans and/ormammals. The salts of the alkali and alkaline-earth metals areparticularly preferred, but also ammonium salts, in particular (mono-)or (di-) sodium, (mono-) or (di-)potassium, magnesium or calcium salts.

The term “salt formed with a physiologically acceptable cation” denotes,according to this invention, salts of at least one of the respectivecompounds as an anion with at least one inorganic cation, which arephysiologically acceptable, in particular when applied to humans and/ormammals. The salts of the alkali and alkaline-earth metals areparticularly preferred, but also ammonium salts, in particular (mono-)or (di-)sodium, (mono-) or (di-)potassium, magnesium or calcium salts.

For a preferred embodiment of the substituted cyclohexyl-1,4-diaminederivatives according to the invention.

R¹ and R² independently of one another represent H; saturated orunsaturated, branched or unbranched, singly or multiply substituted orunsubstituted C₁₋₅ alkyl;

or the radicals R¹ and R² together form a ring and representCH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆,

wherein R¹⁰ represents H; saturated or unsaturated, branched orunbranched, singly or multiply substituted or unsubstituted C₁₋₅ alkyl.

Particularly preferred are substituted cyclohexyl-1,4-diaminederivatives, wherein R¹ and R² independently of one another representCH₃ or H, wherein R¹ and R² do not simultaneously represent H, or R¹ andR² represent CH₂CH₂OCH₂

Also preferred are substituted cyclohexyl-1,4-diamine derivatives,wherein R³ represents respectively unsubstituted or singly or multiplysubstituted cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl,anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl,benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl,pyrimidyl or pyrazinyl; respectively unsubstituted or singly or multiplysubstituted C₅₋₆ cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl,benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl,indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bound by asaturated, unbranched C₁₋₂ alkyl group;

in particular

R³ represents respectively unsubstituted or singly or multiplysubstituted phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl,indolyl, indanyl, benzodioxanyl, benzodioxanyl, pyridyl, pyrimidyl,pyrazinyl or benzothiophenyl; respectively unsubstituted or singly ormultiply substituted phenyl, furyl or thiophenyl bound by a saturated,unbranched C₁₋₂ alkyl group.

Particularly preferred are substituted cyclohexyl-1,4-diaminederivatives, wherein R³ represents respectively substituted orunsubstituted phenyl, phenethyl, thiophenyl, pyridyl or benzyl,particularly preferably phenyl, thienyl, 4-chloro-benzyl, benzyl,3-chloro-benzyl, 4-methylbenzyl, 2-chloro-benzyl, 4-fluoro-benzyl,3-methylbenzyl, 2-methylbenzyl, 3-fluoro-benzyl, 2-fluoro-benzyl orphenethyl.

Also preferred are substituted cyclohexyl-1,4-diamine derivatives,wherein R⁴ represents respectively unsubstituted or singly or multiplysubstituted C₁₋₅ alkyl, cyclohexyl, cyclopentyl, cyclobutyl,cycloheptyl, cyclooctyl, phenyl, benzyl, naphthyl, anthracenyl,thiophenyl, benzothiophenyl, furanyl, isothiazolyl, imidazolyl,triazolyl, triazinyl, pyrazolinonyl, benzofuranyl, benzodioxolanyl,isoquinolinyl, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole,benzotriazole, quinolinyl, carbazole, isoxazolyl, oxazolyl, indolyl,indanyl, benzodioxanyl, indazolyl, benzimidazolyl, pyrrolyl, pyridyl,pyrimidyl or pyrazinyl; respectively unsubstituted or singly or multiplysubstituted phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl,pyridyl, furyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, pyrrolyl,pyrimidyl or pyrazinyl bound by a saturated, unbranched C₁₋₂ alkylgroup,

in particular

R⁴ represents respectively unsubstituted or singly or multiplysubstituted C₁₋₅ alkyl, cyclohexyl, phenyl, benzyl, naphthyl,thiophenyl, benzothiophenyl, furanyl, isothiazolyl, imidazolyl,triazolyl, pyrazolyl, benzofuranyl, isoquinolinyl, benzothiazole,benzotriazole, quinolinyl, isoxazolyl, oxazolyl, indolyl, pyrrolyl,pyridyl, pyrimidyl or pyrazinyl; respectively unsubstituted or singly ormultiply substituted benzyl or phenethyl.

Particularly preferred are substituted cyclohexyl-1,4-diaminederivatives, wherein R⁴ represents respectively unsubstituted or singlyor multiply substituted phenyl, indolyl or methyl.

Also preferred are substituted cyclohexyl-1,4-diamine derivativeswherein X represents branched or unbranched, unsubstituted or singly ormultiply substituted C₁₋₅ alkyl or an unsubstituted or singly ormultiply substituted phenyl or C₃₋₈ cycloalkyl radical bound by abranched or unbranched, substituted or unsubstituted C₁₋₃ alkyl chain.

Also preferred are substituted cyclohexyl-1,4-diamine derivatives,wherein n represents 0.

Most preferred are substituted cyclohexyl-1,4-diamine derivatives fromthe group comprising

-   5-oxo-5-phenyl-valeric acid    4-dimethylamino-4-phenyl-cyclohexyl)-amide-   N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide-   2-(3-benzofuryl-phenyl)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-propionamide-   5-oxo-5-phenyl-pentanoic acid    (4-dimethylamino-4-phenethyl-cyclohexyl)-amide-   2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-propionamide-   5-oxo-5-phenyl-valeric acid    [4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-amide-   2-(3-benzoyl-phenyl)-N-(4-benzyl-4-dimethylamino-cyclohexyl)-propionamide-   N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide-   2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide-   2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-propionamide-   2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-propionamide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-chloro-phenyl)-4-oxo-butyramide-   4-oxo-4-phenyl-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide-   2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-dimethylamino    -4-(3-methyl-benzyl)-cyclohexyl]-acetamide-   4-(4-fluoro-phenyl)-4-oxo-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide-   2-(3-benzoyl-phenyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-propionamide-   5-oxo-5-phenyl-valeric acid    [4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide    N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide-   2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-propionamide-   N-(4-dimethylamino-4-phenethyl-cyclohexyl)-4-oxo-4-phenyl-butyramide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-phenyl-butyramide-   5-oxo-5-phenyl-valeric acid    (4-phenyl-4-piperidin-1-yl-cyclohexyl)-amide-   2-(3-acetyl-2,2-dimethyl-cyclobutyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide-   N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide-   5-oxo-5-phenyl-valeric acid    [4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-amide-   4-(4-chloro-phenyl)-4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-oxo-butyramide-   2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide-   N-(4-dimethylamino-4-phenethyl-cyclohexyl)-2-(1H-indol-3-yl)-2-oxo-acetamide-   2-(3-acetyl-2,2-dimethyl-cyclobutyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide-   N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide-   2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-acetamide-   4-(4-chloro-phenyl)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl-4-oxobutyramide-   N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide-   N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-chloro-phenyl)-4-oxo-butyramide-   5-oxo-5-phenyl-valeric acid    [4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide-   4-(4-chloro-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide-   N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide-   4-(4-chloro-phenyl)-4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-4-oxo-butyramide-   2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-(4-benzyl-4-dimethylamino-cyclohexyl)-acetamide-   5-oxo-5-phenyl-valeric acid    (4-morpholin-4-yl-4-phenyl-cyclohexyl)-amide-   N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide-   N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide-   N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide-   N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide-   7-oxo-octanoic acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide-   N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide-   4-(4-chloro-phenyl)-N-(4-morpholinyl-4-yl-4-phenyl-cyclohexyl)-4-oxo-butyramide-   N-(4-benzyl-4-piperidin-yl-cyclohexyl)-4-oxo-4-phenyl-butyramide-   N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide-   N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide-   7-oxo-octanoic acid    [4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-amide-   6-oxo-heptanoic acid    [4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide-   2-(3-benzoyl-phenyl)-N-(4-benzyl-4-pyrrolidin-1-yl-cyclohexyl)-propionamide-   2-(3-benzoyl-phenyl)-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-propionamide-   6-oxo-heptanoic acid    [4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide-   6-oxo-heptanoic acid (4-morpholin-4-yl-4-phenyl-cyclohexyl)-amide-   4-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramide    hydrochloride, non-polar diastereoisomer-   4-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramide    hydrochloride, polar diastereoisomer-   5-oxo-5-phenylpentanoic acid    (4-dimethylamino-4-phenylcyclohexyl)amide hydrochloride, non-polar    diastereoisomer-   5-oxo-5-phenylpentanoic acid    (4-dimethylamino-4-phenylcyclohexyl)amide hydrochloride, polar    diastereoisomer

in the form of the racemate; the enantiomers, diastereomers, mixtures ofthe enantiomers or diastereomers or an individual enantiomer ordiastereomer; the bases and/or salts of physiologically acceptable acidsor cations.

The substances according to the invention act, for example, on theμ-opioid receptor that is relevant in connection with various diseases,so they are suitable as a pharmaceutical active ingredient in apharmaceutical composition. The invention therefore also relates topharmaceutical compositions containing at least one substitutedcyclohexyl-1,4-diamine derivative according to the invention, andoptionally suitable additives and/or auxiliaries and/or optionallyfurther active ingredients.

The pharmaceutical preparations according to the invention contain, inaddition to at least one substituted cyclohexyl-1,4-diamine derivativeaccording to the invention, optionally suitable additives and/orauxiliaries, therefore also excipients, fillers, solvents, diluents,dyes and/or binders and can be administered as liquid pharmaceuticalpreparations in the form of injection solutions, drops or syrups, assemi-solid pharmaceutical preparations in the form of granules, tablets,pellets, patches, capsules, plasters or aerosols. The choice ofauxiliaries, etc. and the amounts thereof to be used depend on whetherthe pharmaceutical preparation is to be applied orally, perorally,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or topically, forexample to the skin, the mucous membranes or the eyes. Preparations inthe form of tablets, dragees, capsules, granules, drops, juices andsyrups are suitable for oral application, solutions, suspensions, easilyreconstitutable dry preparations and sprays are suitable for parenteral,topical and inhalative applications. Substituted cyclohexyl-1,4-diaminederivatives according to the invention in a deposit, in dissolved formor in a plaster, optionally with the addition of agents to promote skinpenetration, are suitable percutaneous application preparations. Orallyor percutaneously applicable preparation forms can release thesubstituted cyclohexyl-1,4-diamine derivatives according to theinvention after a delay. The substituted cyclohexyl-1,4-diaminederivatives according to the invention may also be applied in the formof parenteral long-acting repositories such as implants or implantedpumps. In principle, further active ingredients known to the personskilled in the art can be added to the pharmaceutical preparationsaccording to the invention.

The amount of active ingredient to be administered to the patient variesas a function of the weight of the patient, the method of application,the indication and the severity of the illness. Conventionally, 0.00005to 50 mg/kg, preferably 0.01 to 5 mg/kg, of at least one substitutedcyclohexyl-1,4-diamine derivative according to the invention areapplied.

For all of the above-mentioned forms of the pharmaceutical compositionaccording to the invention, it is particularly preferred if, in additionto at least one substituted cyclohexyl-1,4-diamine derivative, thepharmaceutical composition contains a further active ingredient, inparticular an opioid, preferably a strong opioid, in particularmorphine, or an anaesthetic, preferably hexobarbital or halothane.

In a preferred form of the pharmaceutical composition, a containedsubstituted cyclohexyl-1,4-diamine derivative according to the inventionis in the form of a pure diastereomer and/or enantiomer, as a racemateor as a non-equimolar or equimolar blend of the diastereomers and/orenantiomers.

Both the ORL1 receptor and the further opioid receptors have beenidentified in particular in the occurrence of pain. Accordingly,substituted cyclohexyl-1,4-diamine derivatives according to theinvention can be used for producing a pharmaceutical composition for thetreatment of pain, in particular acute, neuropathic or chronic pain.

The invention therefore also relates to the use of a substitutedcyclohexyl-1,4-diamine derivative according to the invention forproducing a pharmaceutical composition for treating pain, in particularacute, visceral, neuropathic or chronic pain.

The invention also relates to the use of a substitutedcyclohexyl-1,4-diamine derivative according to the invention for theproduction of a pharmaceutical composition for the treatment of anxiety,stress and stress-related syndromes, depression, epilepsy, Alzheimer'sdisease, senile dementia, catalepsy, general cognitive dysfunction,learning and memory disorders (as a nootropic), withdrawal symptoms,alcohol- and/or drug- and/or medicine abuse and/or dependency, sexualdysfunction, cardiovascular diseases, hypotension, hypertension,tinnitus, pruritus, migraine, hearing difficulties, deficient intestinalmotility, impaired nutrient absorption, anorexia, obesity, locomotivedisorders, diarrhea, cachexia, urinary incontinence, or as a musclerelaxant, anti-convulsive or anaesthetic or for co-administration intreatment with an opioid analgesic or anaesthetic, for diuresis oranti-natriuresis, anxiolysis, for modulation of motor activity, formodulation of neurotransmitter release and treatment ofneurodegenerative diseases associated therewith, for the treatment ofwithdrawal symptoms and/or for reducing opioid addiction potential.

In this case it may be preferred in one of the present uses if asubstituted cyclohexyl-1,4-diamine derivative used is present as a purediastereomer and/or enantiomer, as a racemate or as a non-equimolar orequimolar blend of the diastereomers and/or enantiomers.

The invention also relates to a process for the treatment, in particularin one of the above-mentioned indications, of a non-human mammal orhuman, which or who requires treatment of pain, in particular chronicpain, by administration of a therapeutically effective dose of asubstituted cyclohexyl-1,4-diamine derivative according to theinvention, or of a pharmaceutical composition according to theinvention.

The invention also relates to a process for producing the substitutedcyclohexyl-1,4-diamine derivatives according to the invention, as statedin the following description and examples.

The radicals R⁰¹ and R⁰² have the meaning given for compounds accordingto the invention of formula I for R¹ and R² and, in addition,independently of one another can represent a protecting group. Theremaining radicals have the meaning indicated in formula I:

Basically the various methods, known to a person skilled in the art, forproducing amides are suitable for providing the substances according tothe invention.

The process according to the invention is preferably based on linkingsubstituted cyclohexane-1,4-diamine (WO 02090317) with suitablecarboxylic acids and/or carboxylic acid derivatives, in particularcarboxylic acid chlorides or bromides, and thus converting them intocompounds according to the invention. Polar or non-polar aproticsolvents to which an organic or inorganic auxiliary base, preferablytertiary amines such as triethylamine, diisopropylethylamine or DMAP hasbeen added, are used in reactions with acid chlorides and bromides. Inaddition to amines of this type pyridine, for example, is also suitableas a base and as a solvent. Preferably, acid chlorides are reacted withamines at −30 bis +40° C. in dichloromethane or chloroform in thepresence of triethylamine or pyridine and optionally catalytic amountsof DMAP. The entire range of methods, known to a person skilled in theart, for producing amides is also available for reacting carboxylicacids with a substituted cyclohexane-1,4-diamine (WO 02090317). The useof organic or inorganic dehydrating agents such as a molecular sieve,magnesium sulphate, sulphuric acid or carbodiimides such as DCC or DIC,DIC optionally in the presence of HOBt, is advantageous. These reactionsare also preferably carried out in polar or non-polar aprotic solventsat temperatures between −30 and +110° C., preferably −10 and +40° C. Theprotecting groups are optionally subsequently cleaved.

EXAMPLES

The following examples serve to describe the invention in more detail,but do not limit the general idea of the invention.

The yields of the compounds produced have not been optimised.

All temperatures are uncorrected.

The term “ether” means diethylether, “EE” ethylacetate and “DCM”dichloromethane. The term “equivalents” means amount of substanceequivalents, “mp.” melting point or melting range, “decomp.”decomposition, “RT” room temperature, “abs.” absolute (anhydrous),“rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d”days, “vol. %” volume percent, “m %” mass percent and “M” is anindication of concentration in mol/l.

Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was used as thestationary phase for column chromatography.

The thin-layer chromatography tests were carried out using HPTLCchromatoplates, silica gel 60 F 254, from E. Merck, Darmstadt.

The mixing ratios of eluants for chromatography tests are always givenin volume/volume.

The compounds used in the following were either commercially available,or production thereof is known from the prior art or has been derivedfrom the prior art in a manner obvious to a person skilled in the art.

General Directions:

0.1 mmol of an acid chloride, which was prepared from the correspondingcarboxylic acids by methods known to a person skilled in the art (seeTable 1), was added to 0.1 mmol of the cyclohexane-1,4-diamine in thepresence of 1.05 equivalents triethylamine. The mixture was stirred for12 h and a 1M sodium carbonate solution was then added. The product wasobtained by extraction with 3×2 ml dichloromethane, in each case, andremoval of the solvent.

The carboxylic acids used for the last step of the examples areindicated in Table 1.

TABLE 1 List of examples and diagrams of the carboxylic acids used inthe last synthesis step. Name of example Example Carboxylic acid usedcompound 1

5-oxo-5-phenyl-valericacid 4-dimethylamino-4-phenyl-cyclohexyl)-amide 2

N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide3

2-(3-benzofuryl-phenyl)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-propionamide4

5-oxo-5-phenyl-pentanoicacid(4-dimethylamino-4-phenethyl-cyclohexyl)-amide 5

2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-propionamide6

5-oxo-5-phenyl-valericacid[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-amide 7

2-(3-benzoyl-phenyl)-N-(4-benzyl-4-dimethylamino-cyclohexyl)-propionamide8

N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide9

2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide10

2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-propionamide11

2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-propionamide12

N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-chloro-phenyl)-4-oxo-butyramide13

4-oxo-4-phenyl-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide 14

2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide15

4-(4-fluoro-phenyl)-4-oxo-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide16

2-(3-benzoyl-phenyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-propionamide17

5-oxo-5-phenyl-valericacid[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide 18

N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide19

2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-propionamide20

N-(4-dimethylamino-4-phenethyl-cyclohexyl)-4-oxo-4-phenyl-butyramide 21

N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide22

N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide23

N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-phenyl-butyramide24

5-oxo-5-phenyl-valericacid (4-phenyl-4-piperidin-1-yl-cyclohexyl)-amide25

2-(3-acetyl-2,2-dimethyl-cyclobutyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide26

N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide27

N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide28

5-oxo-5-phenyl-valericacid[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-amide 29

4-(4-chloro-phenyl)-4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-oxo-butyramide30

2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide31

N-(4-dimethylamino-4-phenethyl-cyclohexyl)-2-(1H-indol-3-yl)-2-oxo-acetamide32

2-(3-acetyl-2,2-dimethyl-cyclobutyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide33

N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide34

N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide35

2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-acetamide36

4-(4-chloro-phenyl)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl-4-oxobutyramide37

N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide38

N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-chloro-phenyl)-4-oxo-butyramide39

5-oxo-5-phenyl-valericacid[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide 40

4-(4-chloro-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide41

N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide42

4-(4-chloro-phenyl)-4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-4-oxo-butyramide43

2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-(4-benzyl-4-dimethylamino-cyclohexyl)-acetamide44

5-oxo-5-phenyl-valericacid (4-morpholin-4-yl-4-phenyl-cyclohexyl)-amide45

N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide46

N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide47

N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide48

N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide49

7-oxo-octanoic acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide 50

N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide51

4-(4-chloro-phenyl)-N-(4-morpholinyl-4-yl-4-phenyl-cyclohexyl)-4-oxo-butyramide52

N-(4-benzyl-4-piperidin-yl-cyclohexyl)-4-oxo-4-phenyl-butyramide 53

N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide54

N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide55

7-oxo-octanoic acid[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-amide 56

6-oxo-heptanoic acid[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide 57

2-(3-benzoyl-phenyl)-N-(4-benzyl-4-pyrrolidin-1-yl-cyclohexyl)-propionamide58

2-(3-benzoyl-phenyl)-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-propionamide59

6-oxo-heptanoic acid[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide 60

6-oxo-heptanoic acid (4-morpholin-4-yl-4-phenyl-cyclohexyl)-amide

Example 614-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramidehydrochloride, non-polar diastereoisomer

310 mg 3-(4-chlorobenzoyl) propanoic acid(4-(4-chloro-phenyl)-4-oxobutyric acid, 1 mol equivalent) dissolved in1.6 ml DMF (5 mol equivalents) were added to 350 mg of the non-polardiastereoisomer of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, 230 AlN,N-diisopropylcarbodiimide (DIC, 1 mol equivalent) and 200 μg1-hydroxybenzotriazole (HOBt, 1 mol equivalent) at 0° C. and whilestirring. After three hours at this temperature, the mixture was stirredovernight while heating to room temperature. For working up, one-molarsodium carbonate solution was added (pH >10) and the crude product (855mg) isolated by extraction with ethylacetate/THF (V:V=1:1), subsequentdrying over sodium sulphate and evaporation. The main fraction of 447 mgobtained by column chromatography on silica gel (4.0×18 cm) withmethanol/ethylacetate/n-hexane (V:V:V=1:1:1) was dissolved in 45 mlethylacetate and was converted into the corresponding hydrochloride ofthe non-polar diastereoisomer of4-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramide)by adding 20 μl water and 140 μl chlorotrimethylsilane (353 mg whitesolid, mp. 177-180° C.).

Example 624-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramidehydrochloride, polar diastereoisomer

As described for Example 61, 310 mg 3-(4-chlorobenzoyl) propanoic aciddissolved in 1.6 ml DMF were added to 350 mg of the polardiastereoisomer of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, 230 [LN,N-diisopropylcarbodiimide and 200 μg 1-hydroxybenzotriazole (HOBt) at0° C. and while stirring. After three hours at this temperature, themixture was stirred overnight while heating to room temperature. Forworking up, one-molar sodium carbonate solution was added (pH>10) andthe crude product (1.193 mg) was isolated by extraction withethylacetate/THF (V:V=1:1), subsequent drying over sodium sulphate andevaporation. The main fraction of 413 mg obtained by columnchromatography on silica gel (4.0×18 cm) withmethanol/ethylacetate/n-hexane (V:V:V=1:1:1) was dissolved in 41 mlethylacetate and was converted into the corresponding hydrochloride ofthe polar diastereoisomer of4-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramideby adding 18 μl water and 130 μl chlorotrimethylsilane (321 mg whitesolid).

Example 63 5-oxo-5-phenyl pentanoic acid(4-dimethylamino-4-phenylcyclohexyl)amide hydrochloride, non-polardiastereoisomer

280 mg 4-benzoylbutyric acid (5-oxo-5-phenyl pentanoic acid) dissolvedin 1.4 ml DMF were added to 350 mg of the non-polar diastereoisomer ofN,N-dimethyl-1-phenylcyclohexane-1,4-diamine, 230 μlN,N-diisopropylcarbodiimide and 200 μg 1-hydroxybenzotriazole (HOBt) atabout 5° C. while stirring. After three hours at this temperature, themixture was stirred overnight while heating to room temperature. Forworking up, one-molar sodium carbonate solution was added (pH>10) andthe crude product (674 mg) isolated by extraction with ethylacetate,subsequent drying over sodium sulphate and evaporation. The mainfraction of 295 mg obtained by column chromatography on silica gel(4.0×18 cm) with methanol/ethylacetate/n-hexane (V:V:V=1:1:1) wasdissolved in 135 ml ethylacetate and was converted into thecorresponding hydrochloride of the non-polar diastereoisomer of5-oxo-5-phenyl pentanoic acid (4-dimethylamino-4-phenylcyclohexyl)amideby adding 12 μl water and 90 μl chlorotrimethylsilane (310 mg whitesolid, mp. 127-137° C.).

Example 64 5-oxo-5-phenyl pentanoic acid(4-dimethylamino-4-phenylcyclohexyl)amide hydrochloride, polardiastereoisomer

As described for Example 63, 280 mg 5-oxo-5-phenylpentanoylchloridedissolved in 1.6 ml DMF were added to 350 mg of the polardiastereoisomer of N,N-dimethylamino-1-phenylcyclohexane-1,4-diamine,230 μl N,N-diisopropylcarbodiimide and 200 μg 1-hydroxybenzotriazole(HOBt) at 5° C. while stirring. After three hours at this temperature,the mixture was stirred overnight while heating to room temperature. Forworking up, one-molar sodium carbonate solution was added (pH>10) andthe crude product (794 mg) isolated by extraction with ethylacetate,subsequent drying over sodium sulphate and evaporation. The mainfraction of 410 mg obtained by column chromatography on silica gel(4.0×18 cm) with methanol/ethylacetate/n-hexane (V:V:V=1:1:1) wasdissolved in 41 ml ethylacetate and was converted into the correspondinghydrochloride of the polar diastereoisomer of 5-oxo-5-phenylpentanoicacid (4-dimethylamino-4-phenylcyclohexyl)amide by adding 19 μl water and130 μl chlorotrimethylsilane (322 mg white solid).

Tests on the Efficacy of the Compounds According to the Invention:

Measurement of ORL1 Binding

The cyclohexane derivatives of general formula I were examined in areceptor binding assay with 3H-nociceptin/orphanin FQ with membranes ofrecombinant CHO-ORL1 cells. This test system was carried out accordingto the methods presented by Ardati et al (Mol. Pharmacol., 51, 1997, pp.816-824). The concentration of 3H-nociceptin/orphanin FQ was 0.5 nM inthese tests. The binding assays were carried out with 20 μg membraneprotein per 200 μl batch in 50 mM Hepes, pH 7.4, 10 mM MgCl2 and 1 mMEDTA. The binding with the ORL1 receptor was determined by using 1 mgWGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubation of the batchfor one hour at RT and subsequent measurement in the Triluxscintillation counter (Wallac, Finland). The affinity is shown in Table1 as a nanomolar Ki value in or % inhibition at c=1 μM.

Measurement of μ-binding

The receptor affinity for human μ-opiate receptor was determined in ahomogenous batch in microtitre plates. For this purpose, dilution seriesof the respective substituted cyclohexyl-1,4-diamine derivative to betested were incubated with a receptor membrane preparation (15-40 μgprotein per 250 μl incubation batch) of CHO-K1 cells, which express thehuman μ-opiate receptor (RB-HOM receptor membrane preparation from NEN,Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand[³H]-naloxone (NET719, NEN, Zaventem, Belgium) and 1 mg WGA-SPA beads(wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg,Germany) in a total volume of 250 μl for 90 minutes at room temperature.50 mmol/l tris-HCI were added as an incubation buffer with 0.05% byweight sodium azide and 0.06% by weight bovine serum albumin. 25 μmol/lnaloxone were also added to determine the non-specific binding. At theend of the 90-minute incubation period, the microtitre plates werecentrifuged off for 20 minutes at 1000 g and the radioactivity measuredin a β-counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg,Germany). The percentage displacement of the radioactive ligand from itsbinding with the human μ-opiate receptor at a concentration of the testsubstances of 1 μmol/l was determined and given as a percentageinhibition (% inhibition) of the specific binding. IC₅₀ inhibitionconcentrations, which bring about a 50% displacement of the radioactiveligand, were partially calculated by taking as a basis the percentagedisplacement by various concentrations of the compounds of generalformula I to be tested. Ki values for the test substances were obtainedas a result of conversion by means of the Cheng-Prusoff equation.

Measurement of Serotonin Re-uptake

In order to carry out these in vitro studies, synaptosomes were freshlyisolated from rat brain areas. In each case, what is known as a “P2”fraction, which was prepared in accordance with Gray and Whittaker'sdirections (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88),was used. For the 5HT-uptake, these vesicular particles were isolatedfrom the medulla+pons region of male rat brains.

A detailed description of the method can be found in the literature (M.Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert(1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).

Measurement of Noradrenalin Re-uptake

In order to carry out these in vitro studies, synaptosomes were freshlyisolated from rat brain areas. In each case, what is known as a “P₂”fraction, which was prepared in accordance with the directions of Grayand Whittaker (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76,79-88), was used. For the NA-uptake, these vesicular particles wereisolated from the hypothalamus of male rat brains.

A detailed description of the method can be found in the literature (M.Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B. Wilffert(1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).

The following binding data was determined, by way of example:

Example μ-binding [1 μM], % inhibition 1 100 2 100 3 91 4 88 5 84 6 80 780 8 79 9 79 10 79 11 78 12 72 13 71 14 68 15 68 16 68 17 65 18 62 19 6220 61 21 61 22 60 23 60 24 59 25 58 26 58 27 57 28 56 29 55 30 55 31 5532 55 33 54 34 54 35 54 36 53 37 50 38 50 39 48 40 42 41 42 42 42 43 4144 41 61 92 62 81 63 100 64 89

Example ORL 1-binding [1 μM], % inhibition 1 100 2 91 8 78 61 90 63 99

Example 5HT-uptake [10 μM], % inhibition 61 78 62 49 63 85 64 62

Example NA-uptake [10 μM], % inhibition 61 92 62 55 63 83 64 33

Parenteral Solution of a Substituted cyclohexyl-1,4-diamine DerivativeAccording to the Invention

38 g of one of the substituted cyclohexyl-1,4-diamine derivativesaccording to the invention, here Example 1, was dissolved at roomtemperature in 1 l water for injection purposes and then adjusted toisotonic conditions for injection purposes by adding anhydrous glucose.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A cyclohexyl-1,4-diamine compound corresponding to formula I,

wherein R¹ and R² independently of one another represent H; saturated orunsaturated, branched or unbranched, singly or multiply substituted orunsubstituted C₁₋₅ alkyl; singly or multiply substituted orunsubstituted C₃₋₈ cycloalkyl; or singly or multiply substituted orunsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl bound by C₁₋₃ alkyl;or R¹ and R² together form a ring and represent CH₂CH₂OCH₂CH₂,CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆, wherein R¹⁰ represents H; saturated orunsaturated, branched or unbranched, singly or multiply substituted orunsubstituted C₁₋₅ alkyl; singly or multiply substituted orunsubstituted C₃₋₈ cycloalkyl; singly or multiply substituted orunsubstituted aryl or heteroaryl; or singly or multiply substituted orunsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl bound by C₁₋₃ alkyl;substituted or unsubstituted C(O)phenyl, C(O)heteroaryl, C(O)C₁₋₅ alkyl;R³ represents saturated or unsaturated, branched or unbranched, singlyor multiply substituted or unsubstituted C₁₋₅ alkyl; singly or multiplysubstituted or unsubstituted C₃₋₈ cycloalkyl; unsubstituted or singly ormultiply substituted aryl or heteroaryl; unsubstituted or singly ormultiply substituted aryl, heteroaryl or C₃₋₈ cycloalkyl bound by a C₁₋₃alkyl group; X represents a branched or unbranched, unsubstituted orsingly or multiply substituted alkyl group (CH₂)_(n), aryl or C₃₋₈cycloalkyl or a substituted or unsubstituted aryl or C₃₋₈ cycloalkylbound by a C₁₋₃ alkyl group, where n=0, 1, 2, 3, 4, or 5; R⁴ representssaturated or unsaturated, branched or unbranched, singly or multiplysubstituted or unsubstituted C₁₋₅ alkyl; singly or multiply substitutedor unsubstituted C₃₋₈ cycloalkyl; singly or multiply substituted orunsubstituted aryl or heteroaryl; or singly or multiply substituted orunsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl bound by C₁₋₃ alkyl;or an acid, base, or physiologically acceptable salt thereof.
 2. Thecyclohexyl-1,4-diamine compound of claim 1, wherein said compound ispresent in the form of a pure enantiomer or pure diastereoisomer.
 3. Thecyclohexyl-1,4-diamine compound of claim 1, wherein said compound ispresent in the form of a mixture of stereoisomers.
 4. Thecyclohexyl-1,4-diamine compound of claim 1, wherein said compound ispresent in the form of a racemic mixture.
 5. The cyclohexyl-1,4-diaminecompound of claim 1, wherein R¹ and R² independently of one anotherrepresent H; saturated or unsaturated, branched or unbranched, singly ormultiply substituted or unsubstituted C₁₋₅ alkyl; or R¹ and R² togetherform a ring and represent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or (CH₂)₃₋₆.6. The cyclohexyl-1,4-diamine compound of claim 1, wherein R¹ and R²independently of one another represent CH₃ or H, wherein R¹ and R² donot simultaneously represent H, or R¹ and R² together form a ring andrepresent CH₂CH₂OCH₂CH₂, (CH₂)₄ or (CH₂)₅.
 7. The cyclohexyl-1,4-diaminecompound of claim 1, wherein R³ represents unsubstituted or singly ormultiply substituted cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl,anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl,benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl,pyrimidyl or pyrazinyl; an unsubstituted or singly or multiplysubstituted C₅₋₆ cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl,benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl,indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bound by asaturated, unbranched C₁₋₂ alkyl group.
 8. The cyclohexyl-1,4-diaminecompound of claim 1, wherein R³ represents unsubstituted or singly ormultiply substituted phenyl, furyl, thiophenyl, naphthyl, benzyl,benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyridyl,pyrimidyl, pyrazinyl or benzothiophenyl; or unsubstituted or singly ormultiply substituted phenyl, furyl or thiophenyl bound by a saturated,unbranched C₁₋₂ alkyl group.
 9. The cyclohexyl-1,4-diamine compound ofclaim 1, wherein R³ represents substituted or unsubstituted phenyl,phenethyl, thiophenyl, pyridyl or benzyl.
 10. The cyclohexyl-1,4-diaminecompound of claim 1, wherein R³ represents phenyl, thienyl,4-chloro-benzyl, benzyl, 3-chloro-benzyl, 4-methylbenzyl,2-chloro-benzyl, 4-fluoro-benzyl, 3-methylbenzyl, 2-methylbenzyl,3-fluoro-benzyl, 2-fluoro-benzyl or phenethyl.
 11. Thecyclohexyl-1,4-diamine compound of claim 1, wherein R⁴ representsunsubstituted or singly or multiply substituted C₁₋₅ alkyl, cyclohexyl,cyclopentyl, cyclobutyl, cycloheptyl, cyclooctyl, phenyl, benzyl,naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furanyl,isothiazolyl, imidazolyl, triazolyl, triazinyl, pyrazolyl, benzofuranyl,benzodioxolanyl, isoquinolinyl, phthalazine, benzo[1,2,5]thiadiazole,benzothiazole, benzotriazole, quinolinyl, carbazole, isoxazolyl,oxazolyl, indolyl, indanyl, benzodioxanyl, indazolyl, benzimidazolyl,pyrrolyl, pyridyl, pyrimidyl or pyrazinyl; or unsubstituted or singly ormultiply substituted phenyl, naphthyl, anthracenyl, thiophenyl,benzothiophenyl, pyridyl, furyl, benzofuranyl, indolyl, indanyl,benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bound by a saturated,unbranched C₁₋₂ alkyl group.
 12. The cyclohexyl-1,4-diamine compound ofclaim 1, wherein R⁴ represents unsubstituted or singly or multiplysubstituted C₁₋₅ alkyl, cyclohexyl, cyclopentyl, phenyl, benzyl,naphthyl, thiophenyl, benzothiophenyl, furanyl, isothiazolyl,imidazolyl, triazolyl, pyrazolyl, benzofuranyl, isoquinolinyl,benzothiazole, benzotriazole, quinolinyl, isoxazolyl, oxazolyl, indolyl,pyrrolyl, pyridyl, pyrimidyl or pyrazinyl; or unsubstituted or singly ormultiply substituted benzyl or phenethyl.
 13. The cyclohexyl-1,4-diaminecompound of claim 1, wherein R⁴ represents unsubstituted or singly ormultiply substituted phenyl, indolyl or methyl.
 14. Thecyclohexyl-1,4-diamine compound of claim 1, wherein X representsbranched or unbranched, unsubstituted or singly or multiply substitutedC₁₋₅ alkyl, or an unsubstituted or singly or multiply substituted phenylor C₃₋₈ cycloalkyl bound by a branched or unbranched, substituted orunsubstituted C₁₋₃ alkyl group.
 15. The cyclohexyl-1,4-diamine compoundof claim 1, wherein n represents
 0. 16. The cyclohexyl-1,4-diaminecompound of claim 1, wherein said compound is selected from the groupconsisting of: 5-oxo-5-phenyl-valeric acid4-dimethylamino-4-phenyl-cyclohexyl)-amide;N-(4-dimethylamino-4-thiophen-2-yl-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide;2-(3-benzofuryl-phenyl)-N-(4-dimethylamino-4-phenethyl-cyclohexyl)-propionamide;5-oxo-5-phenyl-pentanoic acid(4-dimethylamino-4-phenethyl-cyclohexyl)-amide;2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-propionamide;5-oxo-5-phenyl-valeric acid[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-amide;2-(3-benzoyl-phenyl)-N-(4-benzyl-4-dimethylamino-cyclohexyl)-propionamide;N-[4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide;2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-acetamide;2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-propionamide;2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-propionamide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-chloro-phenyl)-4-oxo-butyramide;4-oxo-4-phenyl-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide;2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-acetamide;4-(4-fluoro-phenyl)-4-oxo-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-butyramide;2-(3-benzoyl-phenyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-propionamide;5-oxo-5-phenyl-valeric acid[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amideN-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide;2-(3-benzoyl-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-propionamide;N-(4-dimethylamino-4-phenethyl-cyclohexyl)-4-oxo-4-phenyl-butyramide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-oxo-4-phenyl-butyramide;5-oxo-5-phenyl-valeric acid(4-phenyl-4-piperidin-1-yl-cyclohexyl)-amide;2-(3-acetyl-2,2-dimethyl-cyclobutyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-acetamide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide;N-[4-dimethylamino-4-(2-fluoro-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide;5-oxo-5-phenyl-valeric acid[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-amide;4-(4-chloro-phenyl)-4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-oxo-butyramide;2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide;N-(4-dimethylamino-4-phenethyl-cyclohexyl)-2-(1H-indol-3-yl)-2-oxo-acetamide;2-(3-acetyl-2,2-dimethyl-cyclobutyl)-N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-acetamide;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide;N-[4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide;2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-acetamide;4-(4-chloro-phenyl)-N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl-4-oxobutyramide;N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-4-phenyl-butyramide;N-(4-benzyl-4-dimethylamino-cyclohexyl)-4-(4-chloro-phenyl)-4-oxo-butyramide;5-oxo-5-phenyl-valeric acid[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide;4-(4-chloro-phenyl)-N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-oxo-butyramide;N-[4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide;4-(4-chloro-phenyl)-4-dimethylamino-4-(3-fluoro-benzyl)-cyclohexyl]-4-oxo-butyramide;2-(3-acetyl-2,2-dimethylamino-cyclobutyl)-N-(4-benzyl-4-dimethylamino-cyclohexyl)-acetamide;5-oxo-5-phenyl-valeric acid(4-morpholin-4-yl-4-phenyl-cyclohexyl)-amide;N-[4-dimethylamino-4-(2-methyl-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide;N-[4-dimethylamino-4-(3-methyl-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide;N-[4-dimethylamino-4-(4-fluoro-benzyl)-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide;N-[4-(2-chloro-benzyl)-4-dimethylamino-cyclohexyl]-2-(1H-indol-3-yl)-2-oxo-acetamide;7-oxo-octanoic acid (4-benzyl-4-dimethylamino-cyclohexyl)-amide;N-[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide;4-(4-chloro-phenyl)-N-(4-morpholinyl-4-yl-4-phenyl-cyclohexyl)-4-oxo-butyramide;N-(4-benzyl-4-piperidin-yl-cyclohexyl)-4-oxo-4-phenyl-butyramide;N-[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-4-(4-fluoro-phenyl)-4-oxo-butyramide;N-(4-benzyl-4-piperidin-1-yl-cyclohexyl)-4-(4-fluoro-phenyl)-4-oxo-butyramide;7-oxo-octanoic acid[4-dimethylamino-4-(4-methyl-benzyl)-cyclohexyl]-amide; 6-oxo-heptanoicacid [4-(3-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide;2-(3-benzoyl-phenyl)-N-(4-benzyl-4-pyrrolidin-1-yl-cyclohexyl)-propionamide;2-(3-benzoyl-phenyl)-N-(4-phenyl-4-piperidin-1-yl-cyclohexyl)-propionamide;6-oxo-heptanoic acid[4-(4-chloro-benzyl)-4-dimethylamino-cyclohexyl]-amide; 6-oxo-heptanoicacid (4-morpholin-4-yl-4-phenyl-cyclohexyl)-amide;4-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramidehydrochloride, non-polar diastereoisomer;4-(4-chloro-phenyl)-N-(4-dimethylamino-4-phenylcyclohexyl)-4-oxobutyramidehydrochloride, polar diastereoisomer; 5-oxo-5-phenylpentanoic acid(4-dimethylamino-4-phenylcyclohexyl)amide hydrochloride, non-polardiastereoisomer; and 5-oxo-5-phenylpentanoic acid(4-dimethylamino-4-phenylcyclohexyl)amide hydrochloride, polardiastereoisomer.
 17. A process for producing a cyclohexyl-1,4-diaminecompound according to claim 1, comprising the steps of: linking acyclohexane-1,4-diamine with a carboxylic acid corresponding to formulaII

by adding coupling reagents or by activating the carboxylic acid. 18.The process of claim 10, where said process comprises the step ofproducing an acid chloride.
 19. A pharmaceutical formulation comprisingat least one cyclohexyl-1,4-diamine compound according to claim 1 andone or more physiologically acceptable auxiliary substances.
 20. Amethod of producing a pharmaceutical formulation comprising the steps ofcombining a pharmaceutically effective amount of acyclohexyl-1,4-diamine compound according to claim 1 and one or morephysiologically acceptable auxiliary substances.
 21. A method oftreating pain in a mammal, said method comprising administering to saidmammal an effective amount of a compound according to claim
 1. 22. Themethod of claim 21, wherein said pain is acute, neuropathic or chronicpain.
 23. A cyclohexyl-1,4-diamine compound corresponding to formula I,

wherein R¹ and R² independently of one another represent H; saturated orunsaturated, branched or unbranched, singly or multiply substituted orunsubstituted C₁₋₅ alkyl; singly or multiply substituted orunsubstituted C₃₋₈ cycloalkyl; or singly or multiply substituted orunsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl bound by C₁₋₃ alkyl;or R¹ and R² together represent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂ or(CH₂)₃₋₆, wherein R¹⁰ represents H; saturated or unsaturated, branchedor unbranched, singly or multiply substituted or unsubstituted C₁₋₅alkyl; singly or multiply substituted or unsubstituted C₃₋₈ cycloalkyl;singly or multiply substituted or unsubstituted aryl or heteroaryl; orsingly or multiply substituted or unsubstituted aryl, C₃₋₈ cycloalkyl orheteroaryl bound by C₁₋₃ alkyl; substituted or unsubstituted C(O)phenyl,C(O)heteroaryl, C(O)C₁₋₅ alkyl; R³ represents saturated or unsaturated,branched or unbranched, singly or multiply substituted or unsubstitutedC₁₋₅ alkyl; singly or multiply substituted or unsubstituted C₃₋₈cycloalkyl; unsubstituted or singly or multiply substituted aryl orheteroaryl; unsubstituted or singly or multiply substituted aryl,heteroaryl or C₃₋₈ cycloalkyl bound by a C₁₋₃ alkyl group; X representsa branched or unbranched, unsubstituted or singly or multiplysubstituted alkyl group (CH₂)_(n), aryl or C₃₋₈ cycloalkyl or asubstituted or unsubstituted aryl or C₃₋₈ cycloalkyl bound by a C₁₋₃alkyl group, where n=0, 1, 2, 3, 4, or 5; R⁴ represents saturated orunsaturated, branched or unbranched, singly or multiply substituted orunsubstituted C₁₋₅ alkyl; singly or multiply substituted orunsubstituted C₃₋₈ cycloalkyl; singly or multiply substituted orunsubstituted aryl or heteroaryl; or singly or multiply substituted orunsubstituted aryl, C₃₋₈ cycloalkyl or heteroaryl bound by C₁₋₃ alkyl;or an acid, base, solvate or physiologically acceptable salt thereof.24. The cyclohexyl-1,4-diamine compound of claim 23, wherein saidcompound is present in the form of a hydrate.